Toxicological agents & chemicals

1. Toxicological agents & chemicals Chapter 2.2. PetarBulat, MD, PhD, University of Belgrade 9/9/2012

2. Content • Basics of occupational toxicology • Information sources on hazardous substances • Routes of exposure • Excretion • Exposure assessment • Occupational toxicology • Occupational toxicology of mineral dusts • Occupational toxicology of metals • Occupational toxicology of gases • Occupational toxicology of organic solvents • Prevention of toxic effects of hazardous chemicals

3. Information sources on hazardous substances • Material Safety Data Sheet (MSDS) • Toxicology Data Network (TOXNET) • Haz-Map • Chemical Carcinogenesis Research Information System

4. Routes of exposure • Gastrointestinal tract (ingestion) • Lungs (inhalation) • Skin (topical, percutaneous, or dermal) • Parenteral (other than intestinal canal) routes.

5. Routes of exposure • To exert a systemic toxic effect, a hazardous substance must first enter the circulation by crossing the body’s natural barriers. The two main ways this can occur are: • Passive diffusion • Active transport

6. Excretion • The main routes of excretion of hazardous substances are: • Renal (via the kidneys) - for small, water-soluble molecules • Biliary (via the liver and GIT) - is the second most important route of elimination of substances from the body, and for some materials (such as lipid soluble) may be the most important. • Pulmonary (exhalation via the lungs) - an important route of excretion for volatile substances. • Secretory (in fluids such as sweat, semen, tears)- a minor route

7. Exposure assessment • Exposure assessment is the process of estimating or measuring the magnitude, frequency and duration of exposure to an agent. • It could be performed through two basic concepts: • Ambiental (environmental) monitoring • Biological monitoring

8. Ambiental Monitoring • Measurement of an exposure to an agent in: • General workroom ambient • Specific operation • Worker’s breathing zone

9. Ambiental Monitoring • Continuous monitoring • Integrated sampling • Grab (spot) sampling

10. Continuous Monitoring • Provides real-time measurement of contaminant concentration. • Three different types: • Stationary installations with multipoint monitoring capability • Field monitoring instruments (handheld) • Personal monitors

12. Integrated Sampling • Based on collection (and concentration) of sample over period of time to obtain the average exposure in sampling period (operation, whole shift…). • Active sampling • Passive sampling

14. Grab (spot) Sampling • Based on collection of sample at a point in time to evaluate peak exposures. • Grab sampling is also used to: • Measure exposure in intermittent processes • Identify unknown contaminants • Evaluate sources of contamination

16. Biological Monitoring • Measurement conducted in biological sample that evaluate an exposure or biologic effect of that exposure.

17. Biomarkers • Exposure • Effect • Susceptibility

18. Biomarkers Biomarkers of Exposure Biomarkers of Effect Metabolite DNA-Adducts Somatic Mutation Hyperplasia Internal Dose Biologically Active Dose Early Biological Effect Altered Structure/Function Clinical Defects Exposure Susceptibility Wiliam N. Rom. Environmental & Occupational Medicine. 178:1998

19. Biomarkers of Exposure • Measurements of toxin or its specific metabolite in biological sample. • Examples: • Blood lead level • trans,trans-Muconic acid in urine (benzene metabolite) • Ethanol in exhaled air

20. Biomarkers of Effect • Measurement of biological response leading to injury or disease caused by exposure. • Examples: • Acetyl-cholinesterase activity (in case of organophosphate pesticide exposure) • Erythrocyte protoporphyrine level (in case of lead exposure) • Urine b2 microglobuline level (in case of cadmium exposure)

21. Biomarkers of Susceptibility • Indicators signaling unusually high sensitivity to certain exposure. • Exaples: • Activity of enzymes involved in xenobiotic biotransformation (GST, NAT) • Activity of cell DNA repair mechanisms

22. Ambiental vs. Biological Monitoring

23. Ambiental vs. Biological Monitoring

24. Occupational toxicology of mineral dusts-Asbestos • Asbestos is the term for a group of naturally occurring hydrated silicate minerals. The term asbestos is applied to six such minerals that can be grouped into two main categories: • Serpentine group • Chrysotile (white asbestos) • Amphibole group • Amosite (brown asbestos) • Crocidolite (blue asbestos) • Anthophyllite, Tremolite and Actinolite

25. Occupational Exposure to Asbestos • Processes which includes demolishing and/or repair of: • Pipe and boiler lagging • Thermal and acoustic insulation • Insulation boards for fire protection, wall and ceiling panels • Asbestos cement products: corrugated or flat sheeting, rainwater pipes, gutters, tiles, cladding, flues etc.

27. Asbestos Health Effects • Asbestosis-fibrotic pneumoconiosis that causes a progressive loss of elasticity and lung function, normally over many years of asbestos exposure. • Mesothelioma-malignant growth in the pleura or more rarely the peritoneum (it may develop any time from 15 to 50 years after the first exposure to asbestos). • Lung cancer-increased risk in smokers exposed to asbestos.

29. Occupational toxicology of metalsCadmium • Cadmium occurs naturally as cadmium sulphide with zinc blende. It is produced as by-product in zinc, lead and copper production.

30. Exposure to Cadmium • The most important occupational exposures occur during: • Cadmium smelting • Steel alloys production • Recycling of electronic waste • Cigarette smoking is a significant source of cadmium exposure in the general population.

31. Cadmium route of exposure • The main route of cadmium exposure is inhalation (in case of cadmium fumes absorption may reach 40-60% of inhaled cadmium). • Through digestive system only 5% of ingested cadmium is absorbed (in children it could be significantly higher).

32. Cadmium toxicokinetics • Once taken up by the blood, the majority of cadmium is transported bound to proteins, such as Albumin and Metallothionein. • After uptake cadmium is mainly stored in the liver and kidneys. • In case of exposure cessation cadmium liver body burden tends to decrease by shifting to the kidneys. • Cadmium has an extremely long half-life (15-30 years) so it may be detected a long time after exposure has occurred.

33. Cadmium toxicodynamics • Cadmium toxic effects are linked toits reaction with enzyme sulfhydryl groups and consecutive enzyme activity inhibition. • Due to decreased activity of enzymes involved in metabolism and consecutive lack of energy a number of processes in cells are affected. • It has to be mentioned that disturbances of cell metabolism leads also to free radical production and lipid peroxidation damage of cell membranes.

34. Cadmium Health Effects • Acute inhalation of cadmium oxide fumes-irritation of respiratory system. • High exposure to cadmium oxide fume-chemical pneumonitis and oedema in the lungs, which can be fatal. • Chronic cadmium exposure leads to emphysema caused by decreased activity of α1-antitripsine. • Longterm exposure to cadmium leads to kidney damage. Due to accumulation of cadmium in tubular cells and consecutive lack of energy and damage of tubular cells membranes occurs, leading to damage of tubular reabsorption of calcium, phosphate, amino acids, and some low molecular weight proteins (α1-microglobuline and β2-microglobuline). • Cadmium is a human carcinogen causing lung cancer.

35. Cadmium Biological Monitoring • Blood cadmium levels indicate recent exposure to cadmium • Urine cadmium indicate body burdens, although urine levels do respond somewhat to recent exposure. • According to American Conference of Governmental Industrial Hygienists recommendation urine cadmium should be below 5 μg/g creatinine and blood cadmium below 5 μg/L.

36. Cadmium Therapy • Some of the chelating drugs that are beneficial for other toxic metals actually increase cadmium toxicity by mobilizing the cadmium and substantially increasing the renal concentrations and toxicity. • It seems that Monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) was an effective chelating agent for reduction of kidney and liver cadmium when administered either parenterally or orally.

37. Occupational toxicology of gases • For the purpose of occupational toxicology gases are divided in the following groups: • Asphyxiants • Simple asphyxiants: Nitrogen, Methane, Argon. • Chemical asphyxiants: Carbon monoxide, Carbon dioxide, Hydrogen cyanide • Irritants • Upper respiratory tract irritants : Chlorine, Ammonia • Lower respiratory tract irritants : Nitrous oxides

38. Simple asphyxiants • These gases cause adverse health effects by simple asphyxia. • Their effects are the consequence of decreased oxygen level in local atmosphere caused by increased concentration of one of the gases from this group. • If the level of oxygen in the air is reduced below 14% it will cause rapid breathing and tissue damage followed by loss of consciousness and death as oxygen levels reduce further. • Patients intoxicated by simple asphyxiants should be treated with oxygen therapy.

39. Chemical asphyxiants • Chemical asphyxiants are a heterogenous group and each member has its own mechanism of action which at the end leads to asphyxia. • Carbon monoxide is a typical representative for the whole group.

40. Carbon monoxide • Carbon monoxide is a colorless, odorless gas that is produced by the incomplete combustion of organic compounds. • It binds very strongly to haemoglobin, leading to elevated carboxyhaemoglobin levels and consequently a diminished oxygen-carrying capacity of the blood.

41. Carbon monoxide • Acute health effects include giddiness, headache and muscle weakness. • In case of fatal carbon monoxide intoxications victims are quite often found on the ground near doors or windows. It is due to their attempt to open a door or window but due to extreme muscle weakness they could manage it. • In heavily exposed patients hypoxia causes brain damage with memory loss. Also, hypoxia could cause acute heart failure. • Therapy: Patients intoxicated by carbon monoxide should be treated with oxygen therapy as well as other symptomatic and supportive therapy.

42. Irritants • The somewhat arbitrary division into upper and lower respiratory tract irritants is largely based on the solubility. • Highly water soluble gases, such as ammonia, chlorine and sulphur dioxide, exert their main irritant effect on the conjunctiva and upper respiratory tract. This, unless the exposure is prolonged and severe, saves the lungs. • Conversely, gases of low solubility, such as nitrogen oxides and phosgene, have little effect on the upper respiratory tract; their effect is delayed and the main consequence is more or less serious lung damage.

43. Chlorine • Upper respiratory tract irritant. It is used in chemical and pharmaceutical production, water disinfection in swimming pools and water supply as well as in plastics manufacture. • Chlorine reacts with tissue water forming hydrochloric acid, which can cause severe tissue damage in high concentrations. • Acute health effects include severe upper respiratory tract irritation leading to pulmonary oedema and death in those unable to escape its effects. Recovery from an acute exposure may be prolonged. • Chronic effects include bronchitis. • Therapy: Patients intoxicated by chlorine should receive supportive therapy including bronchodilatator therapy. In case of pulmonary oedema high-flow oxygen therapy should be administered.

44. Nitrogen dioxide • Lower respiratory tract irritant. It is used in the manufacture of nitric acid, explosives and jet fuel. It is also generated during some types of welding and diesel engine operation. • Acute health effects of nitrogen dioxide exposure are insidious, due to slow progression of pulmonary irritation some 8 - 24 hours after exposure. Severe exposure can result in death from pulmonary oedema within 48 hours. • Therapy: Intoxicated patients should be carefully monitored at least 48 hours after the exposure. They should receive symptomatic and supportive therapy. In case of pulmonary oedema high-flow oxygen therapy should be administered.

45. Occupational toxicology of organic solvents • Solvents are substances that are capable of dissolving or dispersing one or more other substances. They are a heterogeneous group of substances including: • Aliphatic hydrocarbons • Aromatic hydrocarbons • Alcohols • Amines • Esters • Ethers • Ketones • Nitrated or chlorinated hydrocarbons • Other

46. Occupational toxicology of organic solvents • A number of workers around the globe are exposed to organic solvents used in: paints, varnishes, lacquers, adhesives, glues, and degreasing/cleaning agents, and in the production of dyes, polymers, plastics, textiles, printing inks, agricultural products, and pharmaceuticals. One might assume that almost there is no profession which has not occasional exposure to organic solvents. • Many organic solvents are recognized as: • Carcinogens (e.g., benzene, carbon tetrachloride, trichloroethylene), • Reproductive hazards (e.g., 2-ethoxyethanol, 2-methoxyethanol, methyl chloride), • Neurotoxins (e.g., n-hexane, tetrachloroethylene, toluene).

47. Occupational toxicology of organic solvents • The risk to health from exposure to a solvent will depend on a number of factors including toxicity, exposure level and volatility. • The rate of evaporation of different solvents varies widely. An indication of volatility is given by the vapour pressure – the higher the vapour pressure the greater the potential for significant generation of vapour. • Solvent vapours are heavier than air and in a still environment a saturated vapour cloud will tend to sink towards the floor. However, high concentrations can build up within storage tanks or sumps where air movement is restricted or when large quantities of solvent vapour are released.

48. Occupational toxicology of organic solvents • Organic solvents are generally absorbed by two main routes of entry: • Inhalation of the solvent vapour • Skin absorption. • Solvent vapours are rapidly absorbed through the lungs and enter the bloodstream (causing systemic effects on target organs). • Solvents in contact with the skin can cause local effects as well as being absorbed through the skin into the bloodstream.

49. Occupational toxicology of organic solvents • Acute health effects are like in acute alcoholism. • In the first phase, excitation: the exposed person is hyperactive; he is laughing and singing. • In the second phase, depression symptoms like headache, drowsiness, nausea and dizziness occurs. • In case that exposure continues the person will lose consciousness. • Most severe intoxication is followed by coma and might be fatal.

50. Occupational toxicology of organic solvents • Chronic exposure to organic solvents leads to its chronic adverse health effects. • In case of dermal exposure, skin manifestation may include dermatitis, hyper or hypopigmentation of skin, allergic manifestations etc. • Chronic exposure to organic solvents may cause liver and kidney damage; almost all kinds of haematological changes (decreased or increased number of erythrocytes, leucocytes and thrombocytes). • Quite often as manifestation of peripheral nervous system damage patients are suffering from peripheral neuropathy. • Brain damage is developing insidiously through years of organic solvents exposure. First symptoms like sleepless, nervousness, light depression are rarely recognized. Usually, organic solvents adverse health effects are recognized when more prominent symptoms like irritability, sleep disorders, dementia occurs.